Non-natural macrocyclic inhibitors of histone deacetylases: Design, synthesis, and activity

Journal of Medicinal Chemistry

Volumn 53, Issue 23, 2010, Pages 8387-8399

  Auzzas, Luciana ^a,b   Larsson, Andreas ^a,c   Matera, Riccardo ^a   Baraldi, Annamaria ^a   Deschênes Simard, Benoit ^a   Giannini, Giuseppe ^d   Cabri, Walter ^d   Battistuzzi, Gianfranco ^d   Gallo, Grazia ^d   Ciacci, Andrea ^d   Vesci, Loredana ^d   Pisano, Claudio ^d   Hanessian, Stephen ^a  

^a UNIVERSITÉ DE MONTRÉAL   (Canada)

^b CNR   (Italy)

^c UMEÅ UNIVERSITY   (Sweden)

^d Sigma Tau SpA   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID; ANILINE; APICIDIN; HISTONE DEACETYLASE 6; HISTONE DEACETYLASE INHIBITOR; HYDROXAMIC ACID; MACROCYCLIC COMPOUND; TETRAPEPTIDE;

ARTICLE; CANCER CELL CULTURE; CONTROLLED STUDY; CYTOTOXICITY; DRUG ACTIVITY; DRUG DESIGN; DRUG SELECTIVITY; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN; HUMAN CELL; PHARMACOPHORE;

CELL LINE, TUMOR; DRUG DESIGN; HISTONE DEACETYLASE INHIBITORS; HUMANS; MACROCYCLIC COMPOUNDS; MODELS, MOLECULAR;

EID: 78649876797     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm101092u     Document Type: Article

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65. Non-natural macrocyclic HDAC inhibitors: Mwakwari, S. C.; Guerrant, W.; Patil, V.; Khan, S. I.; Tekwani, B. L.; Gurard-Levin, Z. A.; Mrksich, M.; Oyelere, A. K. Non-Peptide Macrocyclic Histone Deacetylase Inhibitors Derived from Tricyclic Ketolide Skeleton J. Med. Chem. 2010, 53, 6100-6111 and references cited therein
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70. In addition, the binding was stabilized by interactions between the amide bond of the R and S isomers with a conserved water molecule and with an Asp residue (Asp101 in HDAC8), respectively. Furthermore, a H-bond between the methoxy group of the S isomer and Lys33 was observed stabilizing the complex in HDAC8. The Lys residue is present only in this HDAC isoform.
71. Only a hydroxamic acid head can conceivably ensure this premise, at least in principle. For example, certain ketone-based inhibitors were found to be discriminating depending on their chirality (see ref 7a).
72. These residues are conserved among the class I HDAC1, HDAC2, HDAC3, and HDAC8 isoforms and the class II HDAC4 isoform (see ref 7).
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77. Aniline 21a was prepared according to a published procedure: Beckwith, A. L. J.; Gara, W. B. Phosphorylated Sugars. Part XV. Syntheses of 3-Deoxy- d -erythro- and 3-Deoxy- d -threo-hexulosonic Acid 6-(Dihydrogen Phosphates) J. Chem. Soc., Perkin Trans. 1 1975, 593-600
78. Zhao, H.; Thurkauf, A. A Practical and Convenient Synthesis of Methyl 5-Formyl-3-Methoxybenzoate Synth. Commun. 2001, 31, 1921-1926
79. Zimmerman, H. E.; Jones, G., II Exploratory and Mechanistic Organic Photochemistry. XLVII. Photochemistry of a Cyclohexadienone Structurally Incapable of Rearrangement J. Am. Chem. Soc. 1970, 92, 2753-2761
80. Leading references on olefin metathesis: Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003; Vols. 1-3.
81. Grubbs, R. H. Olefin Metathesis Tetrahedron 2004, 60, 7117-7140
82. Deiters, A.; Martin, S. F. Synthesis of Oxygen- and Nitrogen-Containing Heterocycles by Ring-Closing Metathesis Chem. Rev. 2004, 104, 2199-2238 For an excellent review on the RCM with nitrogen-containing compounds, see: Phillips, A. J.; Abell, A. D. Ring-Closing Metathesis of Nitrogen-Containing Compounds: Applications to Heterocycles, Alkaloids, and Peptidomimetics Aldrichimica Acta 1999, 32, 75-89
83. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Synthesis and Activity of a New Generation of Ruthenium-Based Olefin Metathesis Catalysts Coordinated with 1,3-Dimesityl-4,5-dihydroimidazol-2-ylidene Ligands Org. Lett. 1999, 1, 953-956
84. Li, H.; Jiang, X.; Ye, Y.-H.; Fan, C.; Romoff, T.; Goodman, M. 3-(Diethoxyphosphoryloxy)-1,2,3- benzotriazin-4(3H)-one (DEPBT): A New Coupling Reagent with Remarkable Resistance to Racemization Org. Lett. 1999, 1, 91-93
85. Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.; Hoveyda, A. H. A Recyclable Ru-Based Metathesis Catalyst J. Am. Chem. Soc. 1999, 121, 791-799
86. 2 for preventing O -benzyl cleavage, see: Czech, B. P.; Bartsch, R. A. Effect of Amines on O -Benzyl Group Hydrogenolysis J. Org. Chem. 1984, 49, 4076-4078
87. Catley, L.; Weisberg, E.; Tai, Y. T.; Atadja, P.; Remiszewski, S.; Hideshima, T.; Mitsiades, N.; Shringarpure, R.; LeBlanc, R.; Chauhan, D.; Munshi, N. C.; Schlossman, R.; Richardsone, P.; Griffin, J.; Anderson, K. C. NVP-LAQ824 Is a Potent Novel Histone Deacetylase Inhibitor with Significant Activity Against Multiple Myeloma Blood 2003, 102, 2615-2622
88. Remiszewski, S. W. The Discovery of NVP-LAQ824: From Concept to Clinic Curr. Med. Chem. 2003, 10, 2393-2402
89. Screening was performed by Reaction Biology Corp., Malvern, PA.
90. 50(S / R) = 0.08-0.28] can be justified by a preferential interaction between the methoxyphenyl ring of the S isomer and loop 1, which contains a conserved His-Pro motif in these isozymes (Figure SI3 of the Supporting Information).
91. An equivalent stabilization was predicted for the R isomer.
92. Docking of (S)- 35 to HDAC8 accounted for interactions similar to those observed with (S)- 9. An extra stabilization was detected between Phe208 and the anilido ring of (S)- 35.
93. In particular, the S isomer of 37 was predicted to gain a better stabilization than its enantiomeric counterpart, thanks to a favorable interaction between the indole motif and Tyr100 (see Figure SI5 of the Supporting Information).
94. Quite interestingly, no significant N -Boc deprotection of the starting material was detected. The conditions described for this metathesis reaction proved to be nonreproducible in further trials, leading to an even lower yield of macrocycle (S)- 39. Other catalysts (Grubbs' first or second generation) under various conditions (solvents, temperature, additives) were unsuccessful.
95. Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.; Mathre, D. J.; Grabowski, E. J. J. Direct Conversion of Activated Alcohols to Azides Using Diphenyl Phosphorazidate. A Practical Alternative to Mitsunobu Conditions J. Org. Chem. 1993, 58, 5886-5888
96. Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F. Sixty Years of Staudinger Reaction Tetrahedron 1981, 37, 437-472
97. Upadhyaya, D. J.; Barge, A.; Stefania, R.; Cravotto, G. Efficient, Solventless N -Boc Protection of Amines Carried Out at Room Temperature Using Sulfamic Acid as Recyclable Catalyst Tetrahedron Lett. 2007, 48, 8318-8322
98. The formation of homocoupling side products and a significant decomposition of the starting material were observed.
99. Abarbri, M.; Thibonnet, J.; Bérillon, L.; Dehmel, F.; Rottländer, M.; Knochel, P. Preparation of New Polyfunctional Magnesiated Heterocycles Using a Chlorine-, Bromine-, or Iodine-Magnesium Exchange J. Org. Chem. 2000, 65, 4618-4634
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101. Beinhoff, M.; Weigel, W.; Rettig, W.; Bruedgam, I.; Hartl, H.; Schlueter, A. D. Phenylene Alkylene Dendrons with Site-Specific Incorporated Fluorescent Pyrene Probes J. Org. Chem. 2005, 70, 6583-6591
102. Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R. Desulfonylation of aryl alkyl sulfones. Tetrahedron Lett. 1976, 17, 3477 - 3478.
103. With the exception of HDAC8 (Tyr100) and HDAC10 (Phe90), Phe566 in HDAC6 corresponds to nonaromatic and polar amino acids in the other isoforms (F566E in HDAC1 and HDAC2, F566D in HDAC3, F566T in HDAC7, and F566S in HDAC4, HDAC5, and HDAC9) (see ref 7e).
104. Apicidin X-ray: Cambridge Crystallographic Data Centre, deposit CCDC 274844: Kranz, M.; Murray, P. J.; Taylor, S.; Upton, R. J.; Clegg, W.; Elsegood, M. R. J. Solution, Solid Phase and Computational Structures of Apicidin and Its Backbone-Reduced Analogs J. Pept. Sci. 2006, 12, 383-388
105. Horne, W. S.; Olsen, C. A.; Beierle, J. M.; Montero, A.; Ghadiri, M. R. Probing the Bioactive Conformation of an Archetypal Natural Product HDAC Inhibitor with Conformationally Homogeneous Triazole-Modified Cyclic Tetrapeptides Angew. Chem., Int. Ed. 2009, 48, 1-7
106. Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J. T.; Bokesch, H.; Kenney, S.; Boyd, M. R. New Colorimetric Citotoxycity Assay for Anticancer-drug Screening J. Natl. Cancer Inst. 1990, 82, 1107-1112